Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Taxol, a naturally occurring diterpene with antitumor activity, induces tubulin polymerization to generate abnormally stable and nonfunctional microtubules. Previously, we showed that taxol has lipopolysaccharide (LPS)-like effects on macrophages. As LPS is a potent inducer of macrophage cytokine production, we investigated whether a similar effect is exerted by taxol. In a dose-dependent manner, LPS-free taxol induced release of biologically active tumor necrosis factor alpha (TNF) by inflammatory murine macrophages. Taxol-induced production of TNF was inhibitable by interleukin-10. By Northern blot, taxol (10 and 1 microM) induced TNF mRNA expression to an extent similar to LPS. Induction of TNF mRNA by 10 microM taxol was detectable at 45 min of stimulation, maximal at 90 min, and evident for at least 8 h. The same low concentration of taxol also induced interleukin 1 (IL-1) alpha and beta mRNA expression. We conclude that taxol triggers macrophages for TNF and IL-1 production. These LPS-like effects of taxol might contribute to its antitumor activity.
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PMID:Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages. 135 17

Taxol, a microtubule stabilizer with anticancer activity, mimics the actions of lipopolysaccharide (LPS) on murine macrophages in vitro. Recently, it was shown that taxol-induced macrophage activation was inhibited by the LPS antagonist Rhodobacter sphaeroides diphosphoryl lipid A (RsDPLA). To investigate the mechanisms of taxol-induced macrophage activation, the present study focused on the interaction of LPS, RsDPLA, and taxol in the activation of and binding to macrophages. Taxol alone induced murine C3H/He macrophages to secrete tumor necrosis factor alpha (TNF) and to produce nitric oxide (NO) with kinetics similar to that of LPS. Macrophages from LPS-hyporesponsive C3H/HeJ mice, in contrast, did not yield any detectable TNF and NO production in response to LPS or taxol. RsDPLA inhibited taxol-induced TNF and NO production from C3H/He macrophages in a dose-dependent manner. The inhibition by RsDPLA was specific for LPS and taxol in that RsDPLA did not inhibit heat-killed Listeria monocytogenes- or zymosan-induced TNF production. Polymyxin B blocked the inhibitory effect of RsDPLA on taxol-induced TNF production. The inhibitory activity of RsDPLA appeared to be reversible since macrophages still responded to taxol in inducing TNF production after the RsDPLA was washed out with phosphate-buffered saline prior to the addition of taxol. Taxol-induced TNF production was not inhibited by colchicine, vinblastine, or 10-deacetylbaccatine III. A mutant cell line, J7.DEF3, defective in expression of a CD14 antigen, responded equally well to taxol by producing TNF as did the parent J774.1 cells. This suggested that the activation of macrophages by taxol does not require CD14. Taxol-induced TNF production by the mutant cells was also inhibited by RsDPLA. 125I-labeled LPS and 3H-labeled taxol was reported to bind to J774.1 cells predominantly via CD14 and microtubules, respectively. The binding of 125I-labeled LPS to J7.DEF3 cells was about 30 to 40% of that to J774.1 cells. The binding of 125I-LPS to J774.1 cells was inhibited by unlabeled LPS and RsDPLA but not by taxol. On the other hand, 3H-labeled taxol bound to both J774.1 cells and J7.DEF3 cells in similar time- and dose-dependent manners. The binding of [3H]taxol to these cells was inhibited by taxol but not by LPS or RsDPLA. Although the binding studies failed to examine cross competition for binding to macrophages, a possible explanation of these results is that LPS, RsDPLA, and taxol share the same molecule(s) on murine macrophages for their functional receptor(s), which is neither CD14 nor tubulin.
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PMID:CD14 is not involved in Rhodobacter sphaeroides diphosphoryl lipid A inhibition of tumor necrosis factor alpha and nitric oxide induction by taxol in murine macrophages. 752 46

Bacterial lipopolysaccharide (LPS) modulates expression of a variety of genes in macrophages, and additionally activates viral promoters including the HIV-1 LTR. The HIV-1 LTR driving the luciferase reporter gene was stably transfected into the murine macrophage cell line, RAW264. In stably transfected cells, luciferase activity was LPS-dependent. As little as 0.01 ng/ml LPS was sufficient to increase luciferase activity over basal levels with maximal stimulation resulting in a 10- to 20-fold response. The cells also responded to human and murine tumour necrosis factor (TNF alpha). Endogenous TNF alpha was not involved in LPS responses, since pretreatment with alpha-TNF alpha antibody did not affect activation. Induction of HIV-1 LTR activity by LPS occurred independently of phorbol myristate acetate (PMA) sensitive protein kinase C (PKC), since depletion of PKC by prolonged exposure to PMA blocked TNF alpha and PMA responses but was not able to abolish LPS action on these cells. Taxol (5-20 micrograms/ml), a chemotherapeutic agent which mimics LPS action on macrophages, was also able to increase expression of the reporter gene driven by the HIV-1 LTR. However, lower doses of taxol that were not sufficient to trans-activate the LTR or to induce TNF alpha expression were cytotoxic to RAW264 cells suggesting that the cytotoxic and LPS-like activities of taxol were not linked. This cell line provides a convenient method for detecting LPS-like activity and is a useful tool for examining LPS and TNF alpha signalling pathways.
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PMID:RAW264 macrophages stably transfected with an HIV-1 LTR reporter gene provide a sensitive bioassay for analysis of signalling pathways in macrophages stimulated with lipopolysaccharide, TNF-alpha or taxol. 758 58

Taxol, a plant-derived antimitotic, was recently found to mimic several of the effects of endotoxic bacterial lipopolysaccharide on murine macrophages. However, the mechanisms underlying the cell cycle-independent actions of taxol remain unclear. Here, we report that taxol rapidly activated nuclear factor kappa B (NF-kappa B) in mouse peritoneal macrophages. The intranuclear transcription factor complexes contained two NF-kappa B heterodimers, p50/RelA and p50/c-rel. Taxol-induced nuclear translocation of NF-kappa B was inhibited by pyrrolidine dithiocarbamate, an antioxidant, but not by cycloheximide, a protein synthesis inhibitor. The ability of taxol to activate NF-kappa B may help account for its induction of immunoregulatory and cytotoxic cytokines, which in turn may contribute to its antitumor effects.
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PMID:Activation of NF-kappa B in murine macrophages by taxol. 776

Taxol, a microtubule-stabilizing agent, has been shown to have antineoplastic activity against various tumors. In addition, it has been shown that taxol resembles bacterial lipopolysaccharide in its ability to activate macrophages. Recently we have shown that lipopolysaccharide induces the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) in murine B-cell lines. In light of the similarity of taxol and lipopolysaccharide in their effects on macrophages, we tested whether taxol could also induce the expression of GM-CSF in B-cell lines. In the present study we used the murine B-lymphoma cell line M12.4.1. In unstimulated cells, no GM-CSF mRNA was detected, whereas in taxol-stimulated stimulated cells at a concentration of 30 microM, GM-CSF mRNA was induced 4-8 h after stimulation. This induction of GM-CSF mRNA was down-regulated by 10 ng/ml of interleukin 4. Actinomycin D chase experiments revealed that interleukin 4 did not affect the half-life of the taxol-induced GM-CSF cytoplasmic mRNA, nor did it alter GM-CSF gene transcription. Polymerase chain reaction analysis of nuclear RNA, utilizing probes specific for sequences in the first intron of GM-CSF, indicated that taxol enhances accumulation of nuclear precursor RNA and that interleukin 4 decreases this accumulation. The present study shows a novel activity of taxol in inducing the release of the hematopoietic growth factor GM-CSF from B-cells. Since GM-CSF is known to recruit macrophages and enhance their cytotoxicity against tumor cells, our observations suggest that part of the known antitumor activity of taxol may be due to synergistic effects of GM-CSF activity together with direct cytotoxic actions through microtubule stabilization.
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PMID:Taxol induces the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor in murine B-cells by stabilization of granulocyte-macrophage colony-stimulating factor nuclear RNA. 791 12

Taxol is an antitumor drug with cytotoxic properties that correlate with its microtubule-stabilizing activities. It has been reported that taxol parallels lipopolysaccharide in its effects on the induction of tumor necrosis factor-alpha (TNF-alpha) gene expression in macrophages (C. Bogdan and A. Ding, J. Leukocyte Biol., 52: 119-121, 1992; C. L. Manthey, M. E. Brandes, P. Y. Perera, and S. Vogel, J. Immunol., 149: 2459-2465, 1992; J. M. Carboni, C. Singh, and M. A. Tepper, Natl. Cancer Inst. Monogr., 15: 95-101, 1993). Structure-activity studies using taxol and related taxanes have been done to determine the relationship between the effects of taxol on TNF-alpha gene expression and its cytotoxic and microtubule-stabilizing activities. Using Northern blot analysis, it was found that changes in the structure of taxol that did not alter cytotoxicity did prevent the induction of TNF-alpha gene expression. The data presented in this paper demonstrate that the effects of taxol on TNF-alpha gene expression are distinct from its known cytotoxic properties.
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PMID:Relationship between the structure of taxol and other taxanes on induction of tumor necrosis factor-alpha gene expression and cytotoxicity. 795 98

Taxol is the prototype of a new class of microtubule stabilizing agents with promising anticancer activity. Several studies show that taxol mimics the actions of lipopolysaccharide (LPS) on murine macrophages. To investigate the mechanism of taxol-induced macrophage stimulation, we evaluated the ability of Rhodobacter sphaeroides diphosphoryl lipid A (RsDPLA) and SDZ 880.431 to block taxol-induced effects. RsDPLA and SDZ 880.431 are lipid A analogues that lack LPS-like activity, but inhibit the actions of LPS, presumably by blocking critical cellular binding sites. We report that RsDPLA and SDZ 880.431 potently inhibited taxol-induced TNF secretion, gene activation, and protein-tyrosine phosphorylation. The role of microtubules in taxol signaling was investigated. Taxol-induced microtubule bundling in primary and transformed RAW 264.7 macrophages was not blocked by RsDPLA or SDZ 880.431. Taxotere, a semisynthetic taxoid, was more potent than taxol as an inducer of microtubule bundling, but did not induce tumor necrosis factor alpha secretion and gene activation. These data dissociate the microtubule effects of taxol from macrophage stimulation and suggest that taxol stimulates macrophages through an LPS receptor-dependent mechanism. The results underscore the potential of taxol as a tool for studying LPS receptor activation and provide insights into possible therapeutic actions of this new class of drugs.
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PMID:Lipopolysaccharide antagonists block taxol-induced signaling in murine macrophages. 810 63

Taxol is important in the treatment of both primary and drug-resistant ovarian cancer. Although Taxol is known to stabilize microtubules and block cell mitosis, the effectiveness of this drug exceeds that of other antimitotic agents, suggesting it may have an additional mode of action. Stimulated by murine macrophage studies indicating cytokine induction by Taxol, we have investigated proinflammatory cytokine expression in a series of cell lines and recent explants of human ovarian cancer. Taxol induced secretion of interleukin (IL) 8 but not IL-6, IL-1alpha, or IL-1beta in 4 of 10 samples. Induction was dependent on transcriptional activation, and, in contrast to murine macrophage studies, was apparently independent of an active lipopolysaccharide signaling pathway. Confluent cultures secreted as much IL-8 as proliferating cells. Taxol did not induce IL-8 in breast carcinoma, endometrial stromal, or T-lymphocyte or monocyte cultures. We propose that the local expression of this chemokine in vivo may elicit a host response similar in effectiveness to that of cytokine gene therapy. These data are the first to suggest that a chemotherapeutic agent may have a direct effect on transcription of cytokine and/or growth factor genes in ovarian cancer, and that this effect may not be restricted to proliferating tumor cells.
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PMID:Taxol-dependent transcriptional activation of IL-8 expression in a subset of human ovarian cancer. 864 Aug 18

Interaction of bacterial lipopolysaccharide (LPS) with macrophages results in the induction of a cascade of cytokines that mediate the varied effects of LPS. An early intracellular signaling event that follows receptor engagement is the activation of transcription factor NF-kappaB. Nf-kappaB has been shown to be important for the induction of many LPS-inducible cytokine genes, including tumor necrosis factor alpha, interleukin-1beta, and interleukin-6. Previously, we and others have shown that the antitumor agent paclitaxel (Taxol) is able to mimic bacterial LPS in its ability to activate murine macrophages. In this report, we have extended these findings by demonstrating that paclitaxel, like LPS, is able to stimulate the translocation of primarily p50-p65 heterodimers of NF-kappaB to the nucleus. This activation is dose dependent and requires a concentration of > or =5 microM paclitaxel. The kinetics of NF-kappaB activation by paclitaxel are slower than those of LPS: by 15 min poststimulation, LPS-induced NF-kappaB activation was readily detected, whereas the paclitaxel-induced NF-kappaB activation was minimal. Moreover, paclitaxel- and protein-free LPS-induced translocation of NF-kappaB was seen only in macrophages derived from LPS-responsive C3H/OuJ mice and not from the LPS-hyporesponsive C3H/HeJ mice, a finding that is consistent with those of previous genetic studies linking paclitaxel responsiveness to the Lps gene. Finally, the LPS structural antagonist Rhodobacter sphaeroides diphosphoryl lipid A inhibited both LPS-and paclitaxel-induced NF-kappaB activation, suggesting a common receptor component in this activation.
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PMID:Paclitaxel (Taxol)-induced NF-kappaB translocation in murine macrophages. 864 95

Taxol, a microtubule-binding diterpene, mimics many effects of lipopolysaccharide (LPS) on mouse macrophages. The LPS-mimetic effects of taxol appear to be under the same genetic control as responses to LPS itself. Thus we have postulated a role for microtubule-associated proteins (MAP) in the response of macrophages to LPS. Stimulation of macrophages by LPS quickly induces the activation of mitogen-activated protein kinases (MAPK). MAPK are generally considered cytosolic enzymes. Herein we report that much of the LPS-activatable pool of MAPK in primary mouse peritoneal macrophages is microtubule associated. By immunofluorescence, MAPK were localized to colchicine- and nocodazole-disruptible filaments. From both mouse brain and RAW 264.7 macrophages, MAPK could be coisolated with polymerized tubulin. Fractionation of primary macrophages into cytosol-, microfilament-, microtubule-, and intermediated filament-rich extracts revealed that approximately 10% of MAPK but none of MAPK kinase (MEK1A and MEK2) was microtubule bound. Exposure of macrophages to LPS did not change the proportion of MAPK bound to microtubules, but preferentially activated the microtubule-associated pool. These findings confirm the prediction that LPS activates a kinase bound to microtubules. Together with LPS-mimetic actions of taxol and the shared genetic control of responses to LPS and taxol, these results support the hypothesis that a major LPS-signaling pathway in mouse macrophages may involve activation of one or more microtubule-associated kinases.
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PMID:Association of mitogen-activated protein kinases with microtubules in mouse macrophages. 866 46


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